 |
PDBsum entry 1tlc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Methyltransferase
|
PDB id
|
|
|
|
1tlc
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843u89.
|
|
|
Authors
|
|
A.Weichsel,
W.R.Montfort,
J.Cieśla,
F.Maley.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 1995,
92,
3493-3497.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
A folate analogue, 1843U89 (U89), with potential as a chemotherapeutic agent due
to its potent and specific inhibition of thymidylate synthase (TS; EC 2.1.1.45),
greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine
5'-monophosphate (FdUMP) and dUMP to Escherichia coli TS but also that of dGMP,
GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CD
analysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary complex.
The quantitative binding of dGMP relative to GMP, FdUMP, and dUMP was determined
in the presence and absence of U89 by ultrafiltration analysis, which revealed
that although the binding of GMP and dGMP could not be detected in the absence
of U89 both were bound in its presence. The Kd for dGMP was about the same as
that for dUMP and FdUMP, with binding of the latter two nucleotides being
increased by two orders of magnitude by U89. An explanation for the binding of
dGMP was provided by x-ray diffraction studies that revealed an extensive
stacking interaction between the guanine of dGMP and the benzoquinazoline ring
of U89 and hydrogen bonds similar to those involved in dUMP binding. In
addition, binding energy was provided through a water molecule that formed
hydrogen bonds to both N7 of dGMP and the hydroxyl of Tyr-94. Accommodation of
the larger dGMP molecule was accomplished through a distortion of the active
site and a shift of the deoxyribose moiety to a new position. These
rearrangements also enabled the binding of GMP to occur by creating a pocket for
the ribose 2' hydroxyl group, overcoming the normal TS discrimination against
nucleotides containing the 2' hydroxyl.
|
|
|
Secondary reference #1
|
|
|
Title
|
|
Structure, Multiple site binding, And segmental accommodation in thymidylate synthase on binding dump and an anti-Folate.
|
|
|
Authors
|
|
W.R.Montfort,
K.M.Perry,
E.B.Fauman,
J.S.Finer-Moore,
G.F.Maley,
L.Hardy,
F.Maley,
R.M.Stroud.
|
|
|
Ref.
|
|
Biochemistry, 1990,
29,
6964-6977.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
|
|
|
|
